Normal skin epidermis is a complex epithelial tissue containing keratinocytes that are proliferating, differentiating and desquamating, and is stratified such that morphological and functional changes in the keratinocytes occur in an orderly progression. More specifically, the basal layer of the epidermis contains proliferating keratinocytes which synthesize DNA, while the superbasal layers of the epidermis contain highly differentiated keratinocytes which degrade DNA. Thus, the normal epidermis is maintained in a dynamic steady state as proliferation of keratinocytes continually compensates for the loss of cells which are shed from the surface of the skin.
Many common diseases of the skin epidermis, such as psoriasis, squamous cell carcinoma, keratoacanthoma, actinic keratosis and warts, are characterized by localized abnormal proliferation and growth. For example, in psoriasis, which is characterized by scaly, red, elevated plaques on the skin, the keratinocytes are known to proliferate much more rapidly than normal and to differentiate less completely.
While available treatments for such diseases can be effective, their clinical use is often limited by toxicity, either systemic or local. For example, oral methotrexate, which acts to inhibit de novo DNA synthesis, is probably the most effective treatment presently available for psoriasis, yet it is only rarely used for fear of hepatic or bone marrow toxicity Hanno et al., J. Am. Acad. Dermatol. 2:171-174 (1980). Local application of purine and pyrimidine analogs or antimetabolites to diseased skin has either failed to work as expected or has produced intolerable local toxicity. For example, topical methotrexate has been deemed ineffective for treatment of psoriasis. Weinstein et al., Arch Dermatol 117: 388-393 (1981). Topical 5-fluorouracil may be an effective treatment for psoriasis, but is usually considered to be unacceptably irritating. Goette, J. Am Acad Dermatol 4:633-649 (1981).
Many of the chemotherapeutic agents which have been used to treat the hyperproliferative diseases of the epidermis have been inhibitors that block de novo synthesis of nucleotide precursors of DNA. These chemotherapeutic agents have sought to block the de novo synthesis of thymidine monophosphate, which, in the cell, is converted in several steps to thymidine triphosphate, one of the four deoxynucleoside phosphates needed by the cell to synthesize DNA.
Another means by which the cell obtains thymidine for DNA synthesis is by the so-called "salvage" mechanism, whereby thymidine is transported into the cell by cell transport mechanisms, e.g., facilitated diffusion. In contrast to the prior attempts to block de novo synthesis, relatively few attempts have been made to control the "salvage" of nucleosides in the cell for any purpose, and there have been no known attempts to control the "salvage" pathway as a means of treating hyperproliferative diseases of the skin.
Thus, prior attempts to treat hyperproliferative diseases of the skin have proven unsuccessful or have been associated with unacceptable toxicity, and there remains a need for safe and efficacious pharmaceutical compositions and methods for the use thereof which eliminate or moderate the hyperproliferative action of cells of the epidermis in diseases such as psoriasis, actinic keratosis and other hyperplastic and neoplastic conditions of the skin and other organ systems, such as the oral cavity and cervix, which are accessible to direct application of a pharmaceutical agent.